TY - JOUR T1 - SARS-CoV-2 spike protein as a bacterial lipopolysaccharide delivery system in an overzealous inflammatory cascade JF - bioRxiv DO - 10.1101/2021.10.29.466401 SP - 2021.10.29.466401 AU - Firdaus Samsudin AU - Palur Raghuvamsi AU - Ganna Petruk AU - Manoj Puthia AU - Jitka Petrlova AU - Paul MacAry AU - Ganesh S. Anand AU - Artur Schmidtchen AU - Peter J. Bond Y1 - 2021/01/01 UR - http://biorxiv.org/content/early/2021/11/01/2021.10.29.466401.abstract N2 - Accumulating evidence indicates a potential role for bacterial lipopolysaccharide (LPS) in the overactivation of the immune response during SARS-CoV-2 infection. LPS is recognised by Toll-like receptor 4 (TLR4) in innate immunity. Here, we showed that LPS binds to multiple hydrophobic pockets spanning both the S1 and S2 subunits of the SARS-CoV-2 spike (S) protein. LPS binds to the S2 pocket with a lower affinity compared to S1, suggesting its possible role as an intermediate in the TLR4 cascade. Congruently, nuclear factor-kappa B (NF-κB) activation in vitro is strongly boosted by S2. In vivo, however, a boosting effect is observed for both S1 and S2, with the former potentially facilitated by proteolysis. Collectively, our study suggests the S protein may act as a delivery system for LPS in host innate immune pathways. The LPS binding pockets are highly conserved across different SARS-CoV-2 variants and therefore represent potential therapeutic targets.Competing Interest StatementA.S. is a founder and shareholder of in2cure AB, a company developing therapies based on host defence peptides. A patent application related to the present work, with A.S., G.P. and M.P. listed as inventors, has been filed. ER -